Anti-platelet drugs are useful in the treatment of cardiovascular and cerebrovascular diseases. They have been shown to reduce the incidence of vascular events, most importantly, Myocardial Infarction (MI) and stroke. Older people are particularly vulnerable to these diseases, and their risk factors increase with age.
Anti-platelet drugs reduce the aggregation of platelets in the blood, which if left untreated in an atherosclerotic blood vessel, may lead to thromboembolism formation and subsequent cardiovascular events such as stroke or MI. Atherosclerosis is the major cause of vascular events. It can be manifested as coronary disease, cardiovascular disease or peripheral vascular disease (PVD), and some patients suffer from more than one form of the multiple diseases stated above.
It has been shown that fatty deposits found inside the arterial vessels of some asymptomatic individuals as young as 10 years old may later become the site of formation of the atherosclerotic plaques. These plaques are prone to rupture, exposing thrombogenic substances that undergo a cascade of reactions, leading to the formation of a thrombus, which can lead to occlusion of a blood vessel, leading potentially to MI or stroke.
A thrombus is an abnormal clot that develops in blood vessels. Blood flow past the clot likely causes the clot to break away from its attachment to the blood vessel. These freely flowing clots are known as emboli. The emboli do not stop flowing until they plug a narrow portion in the circulatory system, e.g., smaller systemic arteries or arterioles leading to the heart, brain, kidney or lungs. Thrombus and platelet aggregation do not normally form in normal healthy blood vessels. This is because the endothelium releases prostacyclin and nitric oxide, which prevent the formation of thrombi and inhibit platelet aggregation.
Atherosclerosis is a disease of the arteries in which fatty lesions called atheromatous plaques develop on the inside of arterial walls. These plaques are formed by deposition of minute crystals of cholesterol in the intima and smooth muscle of the vessel. The crystals grow larger over time and eventually coalesce to form larger crystals. In addition, the surrounding fibrous and smooth muscle tissues proliferate to form additional layers, which grow over time to form larger and larger plaques. The plaque and the cellular proliferate become so extensive in the arteries that eventually it leads to blockage of the blood flow in the vessel. Further, such extensive amounts of plaque are deposited into the arteries, so that eventually the arteries become stiff and unyielding and they lose their distensibility. In addition, calcium salts often precipitate with the cholesterol and other lipids, leading to calcification, which causes the arteries to form rigid tubes. Because of the degenerative areas in their walls, the arteriosclerotic arteries are easily ruptured. When an atherosclerotic artery ruptures, causing the surface thereof to become rough, the endothelium becomes damaged and cannot release the aforementioned protective mediators. Further, where plaque protrudes into the flowing blood, the roughness of the surface causes clots to develop, and eventually leads to the formation of a thrombus or an embolus.
More specifically, platelets adhere to a ruptured plaque via their glycoprotein IIb receptors, and release a number of active substances such as adenosine diphosphate (ADP), thromboxane A2 (TXA2) and fibrinogen. These agents, among other agents, promote aggregation of platelets. In addition, through a series of reactions, a complex of substances called prothrombin activator is formed in response to the rupture of the blood vessel; the prothrombin activator catalyzes the conversion of prothrombin into thrombin. The thrombin converts fibrinogen into fibrous threads, enmeshing platelets, blood vessels and plasma to form a clot. Because of the occlusion of the blood vessels, blood flows slowly therethrough and forms clots, which can lead to the formation of a thrombus or an embolus.
To combat the adherence of platelets, and inhibit the clotting action, anti-platelet drugs have been administered to patients. While there are a number of such drugs, they can be broadly classified under platelet COX-1 inhibitors, Glycoprotein IIb/IIIa inhibitors and prostacyclin enhancers.
These anti-platelets, which include aspirin, Clopidogrel and dipyridamole, are currently being used to treat MI. Each of these is described below.
Low doses of aspirin have been shown to be of benefit for preventing or treating stroke and MI. As low a maintenance dose of 75 mg per day of aspirin has shown to be effective. Aspirin inhibits the COX enzyme in platelets, which, in turn, inhibits synthesis of TXA2. Aspirin also inhibits prostacyclin. In theory, these two actions should cancel each other, but the endothelium is able to produce more COX enzymes, while the platelets cannot. The endothelium also requires a higher dose of aspirin to inhibit its COX enzyme than that required by the platelets; thus a low dose of aspirin is effective.
However, many patients suffer from serious side effects from aspirin, the most significant being gastrointestinal (“GI”) upset, irritation and bleeding. Also concurrent administration of other non-steroidal anti-inflammatory drugs (“NSAIDs”) significantly increases the occurrences of these side effects. Aspirin also interacts with many other classes of drugs, either making them less effective or more toxic (anti-coagulants, methotrexate and the like).
Clopidogrel has been shown to be somewhat more effective than aspirin in some of the clinical trials. Clopidogrel has a more selective mechanism of action, as it inhibits the binding of the platelet aggregator ADP to its membrane receptors. Unlike aspirin, Clopidogrel does not inhibit COX enzymes. However, the incidence of GI side effects in many clinical trials with Clopidogrel showed that it exhibited the same GI toxicity profile as aspirin. Diarrhea and rashes are more common with Clopidogrel than aspirin. Other side effects include abdominal discomfort, nausea, vomiting, headache, dizziness and thrombocytopenia (abnormally low levels of platelets in the circulating blood).
Similar to aspirin, an increased bleeding is observed when NSAIDs are co-administered with Clopidogrel; and Clopidogrel prolongs the bleeding time of anti-coagulants.
Dipyridamole is used along with aspirin in the prevention of thromboembolism associated with prosthetic heart valves. Also it is used in the prevention of ischemic stroke and transient ischemic attacks, either alone or with aspirin. While the mode of action of Dipyridamole is unclear, it is thought to inhibit the adhesion of platelets to the damaged wall, increase the potency of prostacyclin (which reduces aggregation) and is responsible for other beneficial effects, including vasodilation. But again, dipyridamole has several adverse side effects associated therewith. For example, hepatic failure and elevated hepatic enzymes have been reported in association with dipyridamole administration. Moreover, its administration to patients with underlying coronary disease can aggravate chest pain.